8flp
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8flp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_lividus Conus lividus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FLP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FLP FirstGlance]. <br> | <table><tr><td colspan='2'>[[8flp]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Conus_lividus Conus lividus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FLP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FLP FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8flp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8flp OCA], [https://pdbe.org/8flp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8flp RCSB], [https://www.ebi.ac.uk/pdbsum/8flp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8flp ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8flp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8flp OCA], [https://pdbe.org/8flp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8flp RCSB], [https://www.ebi.ac.uk/pdbsum/8flp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8flp ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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alpha6beta4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions are not fully understood, largely because of a lack of specific ligands. Here, we characterized a novel alpha-conotoxin, LvIC, and designed a series of analogues to probe structure-activity relationships at the alpha6beta4 nAChR. The potency and selectivity of these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes expressed in Xenopus laevis oocytes. One of the analogues, [D1G,DeltaQ14]LvIC, potently blocked alpha6/alpha3beta4 nAChRs (alpha6/alpha3 is a chimera) with an IC(50) of 19 nM, with minimal activity at other nAChR subtypes, including the structurally similar alpha6/alpha3beta2beta3 and alpha3beta4 subtypes. Using NMR, molecular docking, and receptor mutation, structure-activity relationships of [D1G,DeltaQ14]LvIC at the alpha6/alpha3beta4 nAChR were defined. It is a potent and specific antagonist of alpha6beta4 nAChRs that could potentially serve as a novel molecular probe to explore alpha6beta4 nAChR-related neurophysiological and pharmacological functions. | alpha6beta4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions are not fully understood, largely because of a lack of specific ligands. Here, we characterized a novel alpha-conotoxin, LvIC, and designed a series of analogues to probe structure-activity relationships at the alpha6beta4 nAChR. The potency and selectivity of these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes expressed in Xenopus laevis oocytes. One of the analogues, [D1G,DeltaQ14]LvIC, potently blocked alpha6/alpha3beta4 nAChRs (alpha6/alpha3 is a chimera) with an IC(50) of 19 nM, with minimal activity at other nAChR subtypes, including the structurally similar alpha6/alpha3beta2beta3 and alpha3beta4 subtypes. Using NMR, molecular docking, and receptor mutation, structure-activity relationships of [D1G,DeltaQ14]LvIC at the alpha6/alpha3beta4 nAChR were defined. It is a potent and specific antagonist of alpha6beta4 nAChRs that could potentially serve as a novel molecular probe to explore alpha6beta4 nAChR-related neurophysiological and pharmacological functions. | ||
| - | Discovery, Characterization, and Engineering of LvIC, an alpha4/4-Conotoxin That Selectively Blocks Rat alpha6/alpha3beta4 Nicotinic Acetylcholine Receptors.,Zhu X, Wang S, Kaas Q, Yu J, Wu Y, Harvey PJ, Zhangsun D, Craik DJ, Luo S J Med Chem. 2023 | + | Discovery, Characterization, and Engineering of LvIC, an alpha4/4-Conotoxin That Selectively Blocks Rat alpha6/alpha3beta4 Nicotinic Acetylcholine Receptors.,Zhu X, Wang S, Kaas Q, Yu J, Wu Y, Harvey PJ, Zhangsun D, Craik DJ, Luo S J Med Chem. 2023 Feb 9;66(3):2020-2031. doi: 10.1021/acs.jmedchem.2c01786. Epub , 2023 Jan 22. PMID:36682014<ref>PMID:36682014</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
NMR Solution Structure of LvIC analogue
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